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Volume 24,Issue 1,2017 Table of Contents
2017, 24(1):1.
DOI: 10.3872/j.issn.1007-385X.2017.01.001
Abstract:
2017, 24(1):2-5.
DOI: 10.3872/j.issn.1007-385X.2017.01.002
Abstract:
It has experienced nearly a hundred years from presenting a concept of tumor immunity to clinical application of the tumor immunotherapy. Until now, the tumor immunotherapy has become the most promising means of curing malignant tumors which was currently accepted from an adjuvant treatment approach of cancer. Since 2011, multiple blockers of immune checkpoints and durgs of targeted imune cells have achieved favorable clinical efficacy in the treatment of many malignant carcinomas, which has greatly promoted the pre-clinical research on the tumor immunotherapy and its clinical applications. In this review, the development trends of the tumor immunotherapy, faced problems and their corresponding countermeasures were briefly discussed based on the analysis of the current status quo of the tumor immunotherapy in the world and in China.
It has experienced nearly a hundred years from presenting a concept of tumor immunity to clinical application of the tumor immunotherapy. Until now, the tumor immunotherapy has become the most promising means of curing malignant tumors which was currently accepted from an adjuvant treatment approach of cancer. Since 2011, multiple blockers of immune checkpoints and durgs of targeted imune cells have achieved favorable clinical efficacy in the treatment of many malignant carcinomas, which has greatly promoted the pre-clinical research on the tumor immunotherapy and its clinical applications. In this review, the development trends of the tumor immunotherapy, faced problems and their corresponding countermeasures were briefly discussed based on the analysis of the current status quo of the tumor immunotherapy in the world and in China.
2017, 24(1):6-11.
DOI: 10.3872/j.issn.1007-385X.2017.01.003
Abstract:
Currently, chimeric antigen receptor gene-modified T（CAR-T）cell as a viable medicine has achieved exciting efficacy in therapies of blood cancers, which has been widely recognized as a new direction of tumor treatment by the medical community. Throughout the development course of cellular immunotherapy technology, any novel therapy approach needs a continuous improvement process from laboratory to clinical application, does as the CAR-T cell therapy technique. Although it showed unprecedented efficacy in the therapy for hematologic malignancies: the CR rate of advanced recurent relapsed refractory acute lymphoblastic leukemia (ALL) can reach 90%, and the CR rate of chronic lymphocytic leukemia (CLL) and partial B-cell lymphoma can also reach more than 50%, some problems still exsist in the course of treating hematologic malignancies with the CAR-T, such as off-target effect, toxic side effects, short duration of in vivo, high rate of recurrence and so on. It has been conformed that treatment of solid tumors with the CAR-T is safe and effective, but its efficacy remains to be improved. In view of the above problems, the author summarizes six strategies to improve the therapeutic efficacy of the CAR-T: (1) Overcoming defects of T cells in the patients; (2) Selecting optimal culture conditions for the CAR-T cell; (3) Instituting Optimal program of target cell stimulation; (4) Confirming approach of pre-condition by chemotherapy; (5) Achieving the humanized CAR; (6) Enhancing combination of co-stimulatory signals.This article reviewed recent progresses of the CAR-T cytotherapy technique and urgently solved problems in this field.
Currently, chimeric antigen receptor gene-modified T（CAR-T）cell as a viable medicine has achieved exciting efficacy in therapies of blood cancers, which has been widely recognized as a new direction of tumor treatment by the medical community. Throughout the development course of cellular immunotherapy technology, any novel therapy approach needs a continuous improvement process from laboratory to clinical application, does as the CAR-T cell therapy technique. Although it showed unprecedented efficacy in the therapy for hematologic malignancies: the CR rate of advanced recurent relapsed refractory acute lymphoblastic leukemia (ALL) can reach 90%, and the CR rate of chronic lymphocytic leukemia (CLL) and partial B-cell lymphoma can also reach more than 50%, some problems still exsist in the course of treating hematologic malignancies with the CAR-T, such as off-target effect, toxic side effects, short duration of in vivo, high rate of recurrence and so on. It has been conformed that treatment of solid tumors with the CAR-T is safe and effective, but its efficacy remains to be improved. In view of the above problems, the author summarizes six strategies to improve the therapeutic efficacy of the CAR-T: (1) Overcoming defects of T cells in the patients; (2) Selecting optimal culture conditions for the CAR-T cell; (3) Instituting Optimal program of target cell stimulation; (4) Confirming approach of pre-condition by chemotherapy; (5) Achieving the humanized CAR; (6) Enhancing combination of co-stimulatory signals.This article reviewed recent progresses of the CAR-T cytotherapy technique and urgently solved problems in this field.
2017, 24(1):12-17.
DOI: 10.3872/j.issn.1007-385X.2017.01.004
Abstract:
Patients with refractory/relapsed acute lymphoblastic leukemia (ALL) have poor prognosis and short survival time, which has become an international conundrum. Chimeric antigen receptor gene-modified T cell (CAR-T) therapy has been the most promising application targeted immunotherapy so far. CD19-targeted CAR-T (CD19-CAR-T) therapy could reach more than 90% of complete remission rate (CR) for the children and adults with refractory/relapsed ALL, of which efficacy was much higher than that of chemotherapy. However, complications, such as cytokine release syndrome (CRS), serious neurotoxicity (SNT), off-target effect and relapse, seriously impeded its further clinical application. This article mainly reviewed the latest progresses of researches on the manufacture technologies, the conditioning regimens, the cell infusion doses and the prevention and treatment strategies of complications for the CAR-T therapy.
Patients with refractory/relapsed acute lymphoblastic leukemia (ALL) have poor prognosis and short survival time, which has become an international conundrum. Chimeric antigen receptor gene-modified T cell (CAR-T) therapy has been the most promising application targeted immunotherapy so far. CD19-targeted CAR-T (CD19-CAR-T) therapy could reach more than 90% of complete remission rate (CR) for the children and adults with refractory/relapsed ALL, of which efficacy was much higher than that of chemotherapy. However, complications, such as cytokine release syndrome (CRS), serious neurotoxicity (SNT), off-target effect and relapse, seriously impeded its further clinical application. This article mainly reviewed the latest progresses of researches on the manufacture technologies, the conditioning regimens, the cell infusion doses and the prevention and treatment strategies of complications for the CAR-T therapy.
2017, 24(1):18-21.
DOI: 10.3872/j.issn.1007-385X.2017.01.005
Abstract:
To explore the safety and effective doses of CD19 chimeric antigen receptor gene-modified T cells (CD19-CAR-T) for treating the refractory relapsed acute B lymphoblastic leukemia (R/R B-ALL)，as well as side effects and its optimal treatment methods, during July 12, 2015 to November 20, 2016 the 64 patients with R/R B-ALL were treated with the CD19-CAR-T. Among them 55 cases were recurrent primary drug-resistant or refractory patients with B-ALL, 9 cases were refractory positive minimal residual disease (MRD) patients with R/R-ALL confirmed by flow cytometry (FCM). In the early period, the 2 patients dies from treatment-related complications and their efficacy could not evaluated, and the 4 patients did not achieve complete remission (CR). After adjusting inclusion criteria and retransfusion cell numbers of CD19-CAR-T, recently the 33 patients continuously achieved RC, or achieved RC but numbers of their blood cells were not normal without any dead cases. More than 80% patients, who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) after treatment with CD19-CAR-T, continued negative MRD confirmed by FCM until end of the observation, of which efficacy was the same as that of the patients received allo-HSCT at first CR time, and most of the patients who did not receive allo-HSCT had a relapse again within 1 year after CR. In course of the treatment, keys to ensure success of the treatment should be timely and safely handling of cytokines releasing syndromes and various factors of inducing recurrent.
To explore the safety and effective doses of CD19 chimeric antigen receptor gene-modified T cells (CD19-CAR-T) for treating the refractory relapsed acute B lymphoblastic leukemia (R/R B-ALL)，as well as side effects and its optimal treatment methods, during July 12, 2015 to November 20, 2016 the 64 patients with R/R B-ALL were treated with the CD19-CAR-T. Among them 55 cases were recurrent primary drug-resistant or refractory patients with B-ALL, 9 cases were refractory positive minimal residual disease (MRD) patients with R/R-ALL confirmed by flow cytometry (FCM). In the early period, the 2 patients dies from treatment-related complications and their efficacy could not evaluated, and the 4 patients did not achieve complete remission (CR). After adjusting inclusion criteria and retransfusion cell numbers of CD19-CAR-T, recently the 33 patients continuously achieved RC, or achieved RC but numbers of their blood cells were not normal without any dead cases. More than 80% patients, who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) after treatment with CD19-CAR-T, continued negative MRD confirmed by FCM until end of the observation, of which efficacy was the same as that of the patients received allo-HSCT at first CR time, and most of the patients who did not receive allo-HSCT had a relapse again within 1 year after CR. In course of the treatment, keys to ensure success of the treatment should be timely and safely handling of cytokines releasing syndromes and various factors of inducing recurrent.
2017, 24(1):22-29.
DOI: 10.3872/j.issn.1007-385X.2017.01.006
Abstract:
The chimeric antigen receptor gene-modified T cells (CAR-T) technique has constantly made breakthroughs in clinical practice since 2010, especially in the treatment of refractory, relapsed B cell-derived hematologic malignancies (such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, non-Hodgkin’s lymphoma), targeting CD19 molecule of the CAR-T has obtained clinical efficacy which has never been achieved by traditional tumor therapy strategies, and become the most attractive area of the moment in cancer immunotherapy. However, high recurrence rate, toxic side effects and expensive preparation costs of CAR-T, which appeared constantly in the CAR-T cell therapy, have also brought uncertainties to the industrialization of this technique. The article summarized the current development situation of CAR-T cell therapy technique in leading enterprises of the world and thoroughly analyzed challenges to the development of this technique industrialization, as well as evaluated development trend and industrialization prospect of this technique.
The chimeric antigen receptor gene-modified T cells (CAR-T) technique has constantly made breakthroughs in clinical practice since 2010, especially in the treatment of refractory, relapsed B cell-derived hematologic malignancies (such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, non-Hodgkin’s lymphoma), targeting CD19 molecule of the CAR-T has obtained clinical efficacy which has never been achieved by traditional tumor therapy strategies, and become the most attractive area of the moment in cancer immunotherapy. However, high recurrence rate, toxic side effects and expensive preparation costs of CAR-T, which appeared constantly in the CAR-T cell therapy, have also brought uncertainties to the industrialization of this technique. The article summarized the current development situation of CAR-T cell therapy technique in leading enterprises of the world and thoroughly analyzed challenges to the development of this technique industrialization, as well as evaluated development trend and industrialization prospect of this technique.
2017, 24(1):30-37.
DOI: 10.3872/j.issn.1007-385X.2017.01.007
Abstract:
Objective:To investigate the effects of p-hydroxylcinnamaldehyde (CMSP), a novel compound extracted from cochinchina momordica seed, on differentiation of esophageal carcinoma TE-13 cells and its possible mechanism. Methods: FCM was used to evaluate the effect of CMSP (at concentrations of 10, 20, 40 μg/ml) on the apoptosis and cell cycle distribution of TE-13 cells. Wright-Giemsa staining and electron microscope were used to observe the morphological changes of TE-13 cells. RT-qPCR and ELISA were used to evaluate the expressions of tumor associated antigens CEA（carcino-embryonic antigen）and SCC（squamous cell carcinoma antigen）in TE-13 cells after the treatment with CMSP. Influence of different concentrations of CMSP on proliferation and migration of TE-13 cells were determined by colony forming assay and transwell assay. Western blotting was used to evaluate the expression of the proteins in MAPK pathway of TE-13 cells that treated by CMSP (20 μg/ml). Results: CMSP significantly inhibited the growth of esophagus cancer cell lines Kyse30, Te-13, Eca109 and Kyse180 (\[1.6±0.2\]×104 vs \[3.8±0.3\]×104, \[1.7±0.3\]×104 vs \[4.5±0.4\]×104, \[2.5±0.1\]×104 vs \[4.0±04\]×104, \[1.5±0.1\]×104 vs \[2.5±0.3\]×104, all P<0.01), but had no significant effect on normal esophageal epithelial cells (P>0.05). After the treatment with CMSP, (1) the number of TE-13 cells at G0/G1 phase increased in a dose (10, 20, 40 μg/ml) and time （24, 48, 72 h）dependent manner (P<0.01,P<0.05）, while the number of cells at S phase decreased (P<0.01, P<0.05); however, the apoptosis rate showed no obvious change (P>0.05); (2) TE-13 cells showed typical dendrite-like cellular protrusions, and the percentage of such elongated cells was significantly and progressively increased with the increase in CMSP concentration (P<0.05); (3) the expressions of CEA and SCC in TE-13 cells significantly decreased (P<0.01); (4) CMSP significantly inhibited the proliferation and migration ability of TE-13 cells and induced cell differentiation; (5) the protein level of p-P38 was significantly increased while protein levels of p-ERK, p-SPKA/JNK were significantly decreased in TE-13 cells (P<0.01). Conclusion: CMSP suppressed TE-13 cell proliferation and induced the differentiation of TE-13 cells by up-regulating the level of p-P38 and down-regulating the levels of p-ERK, p-SPKA/JNK in MAPK signaling pathway.
Objective:To investigate the effects of p-hydroxylcinnamaldehyde (CMSP), a novel compound extracted from cochinchina momordica seed, on differentiation of esophageal carcinoma TE-13 cells and its possible mechanism. Methods: FCM was used to evaluate the effect of CMSP (at concentrations of 10, 20, 40 μg/ml) on the apoptosis and cell cycle distribution of TE-13 cells. Wright-Giemsa staining and electron microscope were used to observe the morphological changes of TE-13 cells. RT-qPCR and ELISA were used to evaluate the expressions of tumor associated antigens CEA（carcino-embryonic antigen）and SCC（squamous cell carcinoma antigen）in TE-13 cells after the treatment with CMSP. Influence of different concentrations of CMSP on proliferation and migration of TE-13 cells were determined by colony forming assay and transwell assay. Western blotting was used to evaluate the expression of the proteins in MAPK pathway of TE-13 cells that treated by CMSP (20 μg/ml). Results: CMSP significantly inhibited the growth of esophagus cancer cell lines Kyse30, Te-13, Eca109 and Kyse180 (\[1.6±0.2\]×104 vs \[3.8±0.3\]×104, \[1.7±0.3\]×104 vs \[4.5±0.4\]×104, \[2.5±0.1\]×104 vs \[4.0±04\]×104, \[1.5±0.1\]×104 vs \[2.5±0.3\]×104, all P<0.01), but had no significant effect on normal esophageal epithelial cells (P>0.05). After the treatment with CMSP, (1) the number of TE-13 cells at G0/G1 phase increased in a dose (10, 20, 40 μg/ml) and time （24, 48, 72 h）dependent manner (P<0.01,P<0.05）, while the number of cells at S phase decreased (P<0.01, P<0.05); however, the apoptosis rate showed no obvious change (P>0.05); (2) TE-13 cells showed typical dendrite-like cellular protrusions, and the percentage of such elongated cells was significantly and progressively increased with the increase in CMSP concentration (P<0.05); (3) the expressions of CEA and SCC in TE-13 cells significantly decreased (P<0.01); (4) CMSP significantly inhibited the proliferation and migration ability of TE-13 cells and induced cell differentiation; (5) the protein level of p-P38 was significantly increased while protein levels of p-ERK, p-SPKA/JNK were significantly decreased in TE-13 cells (P<0.01). Conclusion: CMSP suppressed TE-13 cell proliferation and induced the differentiation of TE-13 cells by up-regulating the level of p-P38 and down-regulating the levels of p-ERK, p-SPKA/JNK in MAPK signaling pathway.
2017, 24(1):38-42.
DOI: 10.3872/j.issn.1007-385X.2017.01.008
Abstract:
Objective:To investigate the effect of Toll like receptor 1/2(TLR1/2) signaling on CD8+T cells derived from 3LL tumor-bearing mice and its underlying mechanisms. Methods:3LL Lewis lung carcinoma cell line was used to establish tumor-bearing mice model, of which CD8+T cells were purified from the spleen by MACS. CD8+T cells were stimulated in vitro with PBS or TLR1/2 agonist, BLP, and then the gene and protein expression levels of TLRs in CD8+T cells were measured by Real-time PCR and Flow cytometry. What’s more, cytokine secretion and proliferation of CD8+T cells after PBS or BLP stimulation were detected by ELISA and Flow cytometry. The inhibitors of key signal molecules were used to explore the underlying mechanisms of BLP influencing CD8+T cells derived from 3LL-bearing mice. Results: Compared with PBS group, BLP not only greatly increased the expressions of TLR1 and TLR2 genes (TLR1: \[0.353±0.015\] vs \[0.101±0017\], P<0.01; TLR2: (\[0.232±0.031\] vs \[0.080±0.004\], P<0.05) and proteins (P<0.05), but also significantly enhanced the functional cytokine secretion (IFN-γ: \[2 375±305\] vs \[850±50\], P<0.05；IL-2: \[1 600±200\] vs \[350±50\]，P<0.05); in addition, it promoted the proliferation of CD8+T cells (P<0.05). All of these were dependent on NF-κB and P38 pathways. Conclusion: TLR1/2 signaling could directly promote the functions of CD8+T cells derived from 3LL-tumor bearing mice, which might enrich the scope of TLRs and also provide the basis for TLR agonist-based tumor immunotherapy.
Objective:To investigate the effect of Toll like receptor 1/2(TLR1/2) signaling on CD8+T cells derived from 3LL tumor-bearing mice and its underlying mechanisms. Methods:3LL Lewis lung carcinoma cell line was used to establish tumor-bearing mice model, of which CD8+T cells were purified from the spleen by MACS. CD8+T cells were stimulated in vitro with PBS or TLR1/2 agonist, BLP, and then the gene and protein expression levels of TLRs in CD8+T cells were measured by Real-time PCR and Flow cytometry. What’s more, cytokine secretion and proliferation of CD8+T cells after PBS or BLP stimulation were detected by ELISA and Flow cytometry. The inhibitors of key signal molecules were used to explore the underlying mechanisms of BLP influencing CD8+T cells derived from 3LL-bearing mice. Results: Compared with PBS group, BLP not only greatly increased the expressions of TLR1 and TLR2 genes (TLR1: \[0.353±0.015\] vs \[0.101±0017\], P<0.01; TLR2: (\[0.232±0.031\] vs \[0.080±0.004\], P<0.05) and proteins (P<0.05), but also significantly enhanced the functional cytokine secretion (IFN-γ: \[2 375±305\] vs \[850±50\], P<0.05；IL-2: \[1 600±200\] vs \[350±50\]，P<0.05); in addition, it promoted the proliferation of CD8+T cells (P<0.05). All of these were dependent on NF-κB and P38 pathways. Conclusion: TLR1/2 signaling could directly promote the functions of CD8+T cells derived from 3LL-tumor bearing mice, which might enrich the scope of TLRs and also provide the basis for TLR agonist-based tumor immunotherapy.
2017, 24(1):43-47.
DOI: 10.3872/j.issn.1007-385X.2017.01.009
Abstract:
Objective:To explore the regulating effect of miR-765 on inositol polyphosphate 4-phosphatase type Ⅱ（INPP4B） and its influence on the proliferation of hepatocellular carcinoma cells (HCC). Methods:Quantitative Real-time PCR was used to detect the expression of miR-765 in 8 pairs of HCC tissues and adjacent tissues as well as its expression in 8 sets of hepatocellular carcinoma cell lines. Methyl thiazol tetrazolium (MTT) assay was used to detect the influence of miR-765 over-expression on proliferation of HCC cell line. Molecular biology technique was used to construct 3′-UTR reporter gene of INPP4B, and to analyze the regulation effect of miR-765 on INPP4B; Western blotting was used to examine the effect of miR-765 over-expression/silencing on INPP4B protein expression; Colony formation assay together with Western blotting were applied to investigate the specific inhibition of INPP4B on the proliferation of HCC cell lines. Results: miR-765 was highly expressed in HCC tissues and HCC cells (P<0.05). miR-765-mimics transfection significantly increased the proliferation capacity of HCC cell line (\[3.78±1.25\] vs \[2.06±0.47\], P<0.05) . miR-765 could significantly down-regulate the luciferase expression of pGL3-INPP4B-3′UTR reporter gene (\[042±0.01\] vs \[101±0.01\], P<0.05) and also up-regulate the expression of INPP4B (\[0.92±0.04\] vs \[0.42±0.02\], \[0.62±003\]，P<0.05). Specific inhibition of INPP4B significantly promoted the proliferation of HCC cells (\[238.0±173\] vs \[66.33±5.04\], P<0.05). Conclusion: miR-765 promotes the proliferation of HCC cells by down-regulating INPP4B expression.
Objective:To explore the regulating effect of miR-765 on inositol polyphosphate 4-phosphatase type Ⅱ（INPP4B） and its influence on the proliferation of hepatocellular carcinoma cells (HCC). Methods:Quantitative Real-time PCR was used to detect the expression of miR-765 in 8 pairs of HCC tissues and adjacent tissues as well as its expression in 8 sets of hepatocellular carcinoma cell lines. Methyl thiazol tetrazolium (MTT) assay was used to detect the influence of miR-765 over-expression on proliferation of HCC cell line. Molecular biology technique was used to construct 3′-UTR reporter gene of INPP4B, and to analyze the regulation effect of miR-765 on INPP4B; Western blotting was used to examine the effect of miR-765 over-expression/silencing on INPP4B protein expression; Colony formation assay together with Western blotting were applied to investigate the specific inhibition of INPP4B on the proliferation of HCC cell lines. Results: miR-765 was highly expressed in HCC tissues and HCC cells (P<0.05). miR-765-mimics transfection significantly increased the proliferation capacity of HCC cell line (\[3.78±1.25\] vs \[2.06±0.47\], P<0.05) . miR-765 could significantly down-regulate the luciferase expression of pGL3-INPP4B-3′UTR reporter gene (\[042±0.01\] vs \[101±0.01\], P<0.05) and also up-regulate the expression of INPP4B (\[0.92±0.04\] vs \[0.42±0.02\], \[0.62±003\]，P<0.05). Specific inhibition of INPP4B significantly promoted the proliferation of HCC cells (\[238.0±173\] vs \[66.33±5.04\], P<0.05). Conclusion: miR-765 promotes the proliferation of HCC cells by down-regulating INPP4B expression.
2017, 24(1):48-52.
DOI: 10.3872/j.issn.1007-385X.2017.01.010
Abstract:
Objective:To explore the effect and mechanism of Forkhead box Q1 (FOXQ1) gene silencing on migration and invasion abilities of hepatocellular carcinoma cell line SMMC-7721. Methods: FOXQ1-shRNA and NC-shRNA recombinant lentiviral vectors were constructed and transduced into SMMC-7721 cells. There were interfered group, negative group and blank group. Transwell chamber assay was used to detect the abilities of cell migration and invasion. qRT-PCR and Western blotting were used to examine the mRNA and protein expressions of FOXQ1, MMP-2 and MMP-9 in SMMC-7721 cells.Results: FOXQ1 expression level was positively correlated to the migration and invasion abilities of SMMC-7721 cells; Compared with the negative group and blank group, the expression level of FOXQ1 was decreased in interfered group (\[0.34±0.03\] vs \[0.89±0.07\] and \[0.84±0.05\], P<0.05); After FOXQ1gene silencing, the cell migration and invasion abilities of SMMC-7721 cells were significantly decreased (\[9.67±1.15\] vs \[25.67±2.08\] and \[2733±252\]，P<0.05\], in the meanwhile, the expressions of MMP-2 and MMP-9 were down-regulated significantly \[MMP-2: \[0.35±0.04\] vs \[0.61±0.05\] and \[0.65±0.08\]；MMP-9: \[0.40±0.05\] vs \[0.73±0.07\] and \[0.77±006\], all P<0.05). Conclusion: FOXQ1 gene silencing could suppress migration and invasion abilities of hepatocellular carcinoma cell line SMMC-7721. Its mechanism might be related to the down-regulation of MMP-2 and MMP-9.
Objective:To explore the effect and mechanism of Forkhead box Q1 (FOXQ1) gene silencing on migration and invasion abilities of hepatocellular carcinoma cell line SMMC-7721. Methods: FOXQ1-shRNA and NC-shRNA recombinant lentiviral vectors were constructed and transduced into SMMC-7721 cells. There were interfered group, negative group and blank group. Transwell chamber assay was used to detect the abilities of cell migration and invasion. qRT-PCR and Western blotting were used to examine the mRNA and protein expressions of FOXQ1, MMP-2 and MMP-9 in SMMC-7721 cells.Results: FOXQ1 expression level was positively correlated to the migration and invasion abilities of SMMC-7721 cells; Compared with the negative group and blank group, the expression level of FOXQ1 was decreased in interfered group (\[0.34±0.03\] vs \[0.89±0.07\] and \[0.84±0.05\], P<0.05); After FOXQ1gene silencing, the cell migration and invasion abilities of SMMC-7721 cells were significantly decreased (\[9.67±1.15\] vs \[25.67±2.08\] and \[2733±252\]，P<0.05\], in the meanwhile, the expressions of MMP-2 and MMP-9 were down-regulated significantly \[MMP-2: \[0.35±0.04\] vs \[0.61±0.05\] and \[0.65±0.08\]；MMP-9: \[0.40±0.05\] vs \[0.73±0.07\] and \[0.77±006\], all P<0.05). Conclusion: FOXQ1 gene silencing could suppress migration and invasion abilities of hepatocellular carcinoma cell line SMMC-7721. Its mechanism might be related to the down-regulation of MMP-2 and MMP-9.
2017, 24(1):53-57.
DOI: 10.3872/j.issn.1007-385X.2017.01.011
Abstract:
Objective:To detect the expressions of programmed cell death-1 (PD-1) on cytokine-induced killer (CIK) cells derived from umbilical cord blood or peripheral blood from breast cancer patients, as well as to investigate the cytotoxicity of CIK cells on MCF-7 cells. Methods: Umbilical cord blood from healthy pregnant women (n=5) and venous blood from breast cancer patients (n=5) were collected during June 2015 to December 2015 at the 105th Hospital of PLA. The PBMC was isolated, and CIK cells were differentiated and amplified in vitro. The PD-1 expressions on CIK cells derived from two origins at different time points were detected by FCM; CIK cells at 7th, 14th , 21st and 28th days were used for the co-culture with MCF-7 cells, and the cytotoxicity of CIK cells on MCF-7 cells was determined by CCK-8 assay; CIK cell apoptosis after co-culture was observed by AOEB, and the apoptosis rate of CIK cells was determined by FCM. Results：Along with the extending of incubation time, the expressions of PD-1 on CIK cells of both groups increased gradually; PD-1 expression in CIK cells devived from umbilical cord blood at 14th day was lower than that devived from peripheral blood of breast cancer patients (\[38.42±4.76\]% vs \[50.54±3.50\]%,P>0.05), however, the expressions increased in both groups at 21st day and the difference between two groups was not statistically significant (P>005). Cytotoxicity rates of the CIK cells on the MCF-7 cell in the two groups at 7th ，14th ，21st and 28th days after co-culture were (18.54±3.54)% and (21.74±4.27）%，（71.86±16.86）% and（58.78±24.25）%，（44.32±2687）% and （43.96±26.04）% as well as （43.24±24.27）% and （40.28±23.69）% respectively, and among them the cytotoxicity of the CIK cells from umbilical cord blood at 14th day of the culturing was the highest (P<0.05). According to the analysis, there was a positive correlation between PD-1 expression and CIK cell apoptosis(r=0.971,r=0.900, all P<0.01), and a negative correlation between PD-1 expression and CIK cytotoxicity rate (r=-0.865，r=-0.885, all P<0.01). Conclusion：The activated CIK cells had high PD-1 expression，and CIK cells from patients with breast cancer had higher PD-1 expression than CIK cells from umbilical cord blood. The apoptosis rates of CIK cells at 14th day of culture were in both groups lower, and possessed higher cytotoxicities.
Objective:To detect the expressions of programmed cell death-1 (PD-1) on cytokine-induced killer (CIK) cells derived from umbilical cord blood or peripheral blood from breast cancer patients, as well as to investigate the cytotoxicity of CIK cells on MCF-7 cells. Methods: Umbilical cord blood from healthy pregnant women (n=5) and venous blood from breast cancer patients (n=5) were collected during June 2015 to December 2015 at the 105th Hospital of PLA. The PBMC was isolated, and CIK cells were differentiated and amplified in vitro. The PD-1 expressions on CIK cells derived from two origins at different time points were detected by FCM; CIK cells at 7th, 14th , 21st and 28th days were used for the co-culture with MCF-7 cells, and the cytotoxicity of CIK cells on MCF-7 cells was determined by CCK-8 assay; CIK cell apoptosis after co-culture was observed by AOEB, and the apoptosis rate of CIK cells was determined by FCM. Results：Along with the extending of incubation time, the expressions of PD-1 on CIK cells of both groups increased gradually; PD-1 expression in CIK cells devived from umbilical cord blood at 14th day was lower than that devived from peripheral blood of breast cancer patients (\[38.42±4.76\]% vs \[50.54±3.50\]%,P>0.05), however, the expressions increased in both groups at 21st day and the difference between two groups was not statistically significant (P>005). Cytotoxicity rates of the CIK cells on the MCF-7 cell in the two groups at 7th ，14th ，21st and 28th days after co-culture were (18.54±3.54)% and (21.74±4.27）%，（71.86±16.86）% and（58.78±24.25）%，（44.32±2687）% and （43.96±26.04）% as well as （43.24±24.27）% and （40.28±23.69）% respectively, and among them the cytotoxicity of the CIK cells from umbilical cord blood at 14th day of the culturing was the highest (P<0.05). According to the analysis, there was a positive correlation between PD-1 expression and CIK cell apoptosis(r=0.971,r=0.900, all P<0.01), and a negative correlation between PD-1 expression and CIK cytotoxicity rate (r=-0.865，r=-0.885, all P<0.01). Conclusion：The activated CIK cells had high PD-1 expression，and CIK cells from patients with breast cancer had higher PD-1 expression than CIK cells from umbilical cord blood. The apoptosis rates of CIK cells at 14th day of culture were in both groups lower, and possessed higher cytotoxicities.
2017, 24(1):58-63.
DOI: 10.3872/j.issn.1007-385X.2017.01.012
Abstract:
Objective:To investigate the mechanism of P53 regulating stem cell characteristics of lung adenocarcinoma A549 cells. Methods: Carcinoma tissues and relevant para-carcinoma tissues from 30 non-small cell lung carcinoma (NSCLC) patients who underwent surgical resection at No.85 Military Hospital from March 2014 to December 2015 were collected for this study; Levels of miR-145 in collected tissues were determined by Real-time PCR. Human P53 gene eukaryotic expression vector (pcDNA3.1-P53), mutant vector \[pcDNA3.1-P53R273H(CGT-CAT)\] and siRNA that trageting P53 (P53-siRNA) were constructed and transfected into A549 cells. The cells were divided into transfection group (vector or NC-siRNA) and experiment group (Flag-P53 or P53-siRNA). Western blotting was used to examine P53 protein over-expression and interference efficiency; Real-time PCR was used to determine the expressions of miR-145 and OCT4. Dual-luciferase reporter and Western blotting were used to confirm that miR-145 directly targeted OCT4 in A549 cells. Results: Compared with para-carcinoma tissues, miR-145 was obviously decreased in NSCLC samples (\[231±013\] vs \[3.51±0.27\], P<0.01), and P53 significantly promoted miR-145 expression in A549 cells (\[184±0.14\] vs \[1.00±0.00\], P<0.01); miR-145 mimics significantly inhibited the activity of pGAL3-OCT4-3′-UTR (P<0.01) and protein expression of OCT4 (P<0.05) in A549 cells. Additionally, miR-145 inhibitor transfection further increased OCT4 expression and reversed the inhibitory effect of P53 on stem cell characteristics of A549 cells.Conclusion: P53 down-regulats OCT4 expression by promoting miR-145 expression, and further suppresses the stem cell characteristics of A549 cells, which might be a new and safe treatment approach for NSCLC.
Objective:To investigate the mechanism of P53 regulating stem cell characteristics of lung adenocarcinoma A549 cells. Methods: Carcinoma tissues and relevant para-carcinoma tissues from 30 non-small cell lung carcinoma (NSCLC) patients who underwent surgical resection at No.85 Military Hospital from March 2014 to December 2015 were collected for this study; Levels of miR-145 in collected tissues were determined by Real-time PCR. Human P53 gene eukaryotic expression vector (pcDNA3.1-P53), mutant vector \[pcDNA3.1-P53R273H(CGT-CAT)\] and siRNA that trageting P53 (P53-siRNA) were constructed and transfected into A549 cells. The cells were divided into transfection group (vector or NC-siRNA) and experiment group (Flag-P53 or P53-siRNA). Western blotting was used to examine P53 protein over-expression and interference efficiency; Real-time PCR was used to determine the expressions of miR-145 and OCT4. Dual-luciferase reporter and Western blotting were used to confirm that miR-145 directly targeted OCT4 in A549 cells. Results: Compared with para-carcinoma tissues, miR-145 was obviously decreased in NSCLC samples (\[231±013\] vs \[3.51±0.27\], P<0.01), and P53 significantly promoted miR-145 expression in A549 cells (\[184±0.14\] vs \[1.00±0.00\], P<0.01); miR-145 mimics significantly inhibited the activity of pGAL3-OCT4-3′-UTR (P<0.01) and protein expression of OCT4 (P<0.05) in A549 cells. Additionally, miR-145 inhibitor transfection further increased OCT4 expression and reversed the inhibitory effect of P53 on stem cell characteristics of A549 cells.Conclusion: P53 down-regulats OCT4 expression by promoting miR-145 expression, and further suppresses the stem cell characteristics of A549 cells, which might be a new and safe treatment approach for NSCLC.
13 Curative efficacy of DC-CIK cells on the patients with advanced metastatic nasopharyngeal carcinoma
2017, 24(1):64-67.
DOI: 10.3872/j.issn.1007-385X.2017.01.013
Abstract:
Objective:To evaluate the curative efficacy of DC-CIK cells on the patients with advanced metastatic nasopharyngeal carcinoma. Methods: Twenty nine patients with advanced metastatic nasopharyngeal carcinoma treated with DC-CIK cells in Department of Tumor Biotherapy, the 81st Hospital of PLA during August 2011 to June 2015 were retrospectively analyzed. Changes of EB virus VCA-IgA antibody level and lymphocyte subsets before and after DC-CIK cells treatment, as well as its curative efficacy and safety were observed. Results: After the treatment with DC-CIK cells, the objective remission rate of the 29 patients was 0, disease control rate of the patients was 65.5%, media survival time of the patients was 42 months, and the 1-4 years survival rates were 68.0% for all. All the patients had no serious adverse reactions. EB virus VCA-IgA antibody in peripheral blood of the patients after the treatment was significantly lower than that before the treatment (\[30.88±3.91\] U/ml vs \[49.86±5.02\] U/ml, P<005). After the treatment with DC-CIK cells, CD8+ T cells numbers were obviously increased (P<0.05) with the ratio of CD4+/CD8+T significantly decreased (P<0.05). Conclusion: DC-CIK cells immunotherapy for the patients with advanced metastatic nasopharyngeal carcinoma might be safe and feasible, and could produce some clinical efficacy.
Objective:To evaluate the curative efficacy of DC-CIK cells on the patients with advanced metastatic nasopharyngeal carcinoma. Methods: Twenty nine patients with advanced metastatic nasopharyngeal carcinoma treated with DC-CIK cells in Department of Tumor Biotherapy, the 81st Hospital of PLA during August 2011 to June 2015 were retrospectively analyzed. Changes of EB virus VCA-IgA antibody level and lymphocyte subsets before and after DC-CIK cells treatment, as well as its curative efficacy and safety were observed. Results: After the treatment with DC-CIK cells, the objective remission rate of the 29 patients was 0, disease control rate of the patients was 65.5%, media survival time of the patients was 42 months, and the 1-4 years survival rates were 68.0% for all. All the patients had no serious adverse reactions. EB virus VCA-IgA antibody in peripheral blood of the patients after the treatment was significantly lower than that before the treatment (\[30.88±3.91\] U/ml vs \[49.86±5.02\] U/ml, P<005). After the treatment with DC-CIK cells, CD8+ T cells numbers were obviously increased (P<0.05) with the ratio of CD4+/CD8+T significantly decreased (P<0.05). Conclusion: DC-CIK cells immunotherapy for the patients with advanced metastatic nasopharyngeal carcinoma might be safe and feasible, and could produce some clinical efficacy.
14 Progress of clinical translational research on WT1-targeted active immunotherapy for malignant tumor
2017, 24(1):68-72.
DOI: 10.3872/j.issn.1007-385X.2017.01.014
Abstract:
恶性肿瘤的主动特异性免疫治疗是针对肿瘤细胞相关的抗原靶点，设计使机体产生特异性免疫，从而定向杀灭肿瘤细胞的方法。成肾细胞瘤1（nephroblastoma or Wilm’s tumor 1，WT1）是2009年美国国家癌症研究所（National Cancer Institute, NCI）评估所得的最佳恶性肿瘤抗原。目前，国际上已有多个以WT1为靶点的恶性肿瘤的主动特异性免疫治疗项目进入了临床转化研究阶段，主要包括多肽疫苗、DC疫苗和T细胞产品三类，其中galinpepimut-S、WT-4869、Vaccell等疫苗均能使恶性肿瘤患者的总生存期大大延长，同时安全性良好。因此以WT1为靶点的恶性肿瘤的主动特异性免疫治疗是恶性肿瘤治疗的一个有前景的发展方向。本文从WT1多肽疫苗、DC疫苗及T细胞产品三个方面介绍近年来国内外临床转化研究的进展。
恶性肿瘤的主动特异性免疫治疗是针对肿瘤细胞相关的抗原靶点，设计使机体产生特异性免疫，从而定向杀灭肿瘤细胞的方法。成肾细胞瘤1（nephroblastoma or Wilm’s tumor 1，WT1）是2009年美国国家癌症研究所（National Cancer Institute, NCI）评估所得的最佳恶性肿瘤抗原。目前，国际上已有多个以WT1为靶点的恶性肿瘤的主动特异性免疫治疗项目进入了临床转化研究阶段，主要包括多肽疫苗、DC疫苗和T细胞产品三类，其中galinpepimut-S、WT-4869、Vaccell等疫苗均能使恶性肿瘤患者的总生存期大大延长，同时安全性良好。因此以WT1为靶点的恶性肿瘤的主动特异性免疫治疗是恶性肿瘤治疗的一个有前景的发展方向。本文从WT1多肽疫苗、DC疫苗及T细胞产品三个方面介绍近年来国内外临床转化研究的进展。
2017, 24(1):73-82.
DOI: 10.3872/j.issn.1007-385X.2017.01.015
Abstract:
肝细胞癌（hepatocellular carcinoma，HCC）发病率和病死率高，严重威胁人类健康，但目前HCC治疗方法效果较差，术后易复发，亟待研制有效的治疗方案。研究发现HCC的发生发展与肿瘤细胞的免疫逃逸密切相关，恢复患者免疫系统对癌细胞的杀伤能力是其治疗关键。免疫疗法作为近年来热门的肿瘤治疗方案，其核心在于利用各种方法恢复肿瘤患者原本受抑的免疫系统对肿瘤细胞的特异性识别及杀伤能力。免疫治疗方法主要有免疫检查点调控、肿瘤疫苗、免疫靶向疗法、过继性细胞回输等。但是由于肝固有的免疫抑制微环境以及HCC发生机制的多样性，HCC免疫治疗效果个体差异大、疗效有待加强。运用不同类型的免疫疗法或将免疫疗法和其他方法相结合将是未来HCC治疗的发展方向。本文主要就近年来HCC免疫治疗的相关机制和研究进展作一综述。
肝细胞癌（hepatocellular carcinoma，HCC）发病率和病死率高，严重威胁人类健康，但目前HCC治疗方法效果较差，术后易复发，亟待研制有效的治疗方案。研究发现HCC的发生发展与肿瘤细胞的免疫逃逸密切相关，恢复患者免疫系统对癌细胞的杀伤能力是其治疗关键。免疫疗法作为近年来热门的肿瘤治疗方案，其核心在于利用各种方法恢复肿瘤患者原本受抑的免疫系统对肿瘤细胞的特异性识别及杀伤能力。免疫治疗方法主要有免疫检查点调控、肿瘤疫苗、免疫靶向疗法、过继性细胞回输等。但是由于肝固有的免疫抑制微环境以及HCC发生机制的多样性，HCC免疫治疗效果个体差异大、疗效有待加强。运用不同类型的免疫疗法或将免疫疗法和其他方法相结合将是未来HCC治疗的发展方向。本文主要就近年来HCC免疫治疗的相关机制和研究进展作一综述。
2017, 24(1):83-88.
DOI: 10.3872/j.issn.1007-385X.2017.01.016
Abstract:
Ⅰ型干扰素（interferon，IFN）具有抵御病毒感染和复制的功能，因而在抗病毒免疫应答中发挥关键作用。近年来的研究发现，Ⅰ型IFN在抑制肿瘤发生发展中也起重要作用，包括对肿瘤细胞的直接抑制作用，以及通过增强抗肿瘤免疫应答进而抑制肿瘤发生发展。此外，Ⅰ型IFN也是临床肿瘤治疗的重要手段，其对肿瘤放化疗和免疫治疗等均发挥重要的促进作用。同时，Ⅰ型IFN治疗的敏感性和毒副作用等问题也为IFN治疗提出了新的挑战。本文综述了Ⅰ型IFN抑制肿瘤发生发展、与抗肿瘤治疗及其面临的挑战等新近研究进展。
Ⅰ型干扰素（interferon，IFN）具有抵御病毒感染和复制的功能，因而在抗病毒免疫应答中发挥关键作用。近年来的研究发现，Ⅰ型IFN在抑制肿瘤发生发展中也起重要作用，包括对肿瘤细胞的直接抑制作用，以及通过增强抗肿瘤免疫应答进而抑制肿瘤发生发展。此外，Ⅰ型IFN也是临床肿瘤治疗的重要手段，其对肿瘤放化疗和免疫治疗等均发挥重要的促进作用。同时，Ⅰ型IFN治疗的敏感性和毒副作用等问题也为IFN治疗提出了新的挑战。本文综述了Ⅰ型IFN抑制肿瘤发生发展、与抗肿瘤治疗及其面临的挑战等新近研究进展。
2017, 24(1):89-96.
DOI: 10.3872/j.issn.1007-385X.2017.01.017
Abstract:
胸腺基质淋巴细胞生成素（thymic stromal lymphopoietin，TSLP）是一种主要由皮肤、肺、胸腺与胃肠道等器官的上皮细胞分泌的与IL-7类似的炎性细胞因子。TSLP是一种多功能的细胞因子，可以作用于多种细胞如T细胞、B细胞、DC和肿瘤细胞等，具有重要的生物学功能。近年来，越来越多的研究表明，TSLP能够调控肿瘤的发生发展。一方面，TSLP在结肠癌、皮肤癌以及初期乳腺癌、胰腺癌的发展阶段发挥了重要的抗肿瘤作用；另一方面，TSLP在胃癌、肺癌、子宫颈癌和急性淋巴细胞白血病等恶性肿瘤的发生发展过程中发挥促进肿瘤进展的作用，提示TSLP可作为相关肿瘤治疗的潜在靶点。本文综述了近年来TSLP及其信号通路，以及其与乳腺癌、胰腺癌、子宫颈癌、胃癌、结肠癌、肺癌、皮肤癌、B细胞急性淋巴细胞白血病等多种恶性肿瘤发生发展的关系的研究进展，旨在为相关肿瘤的诊断和治疗提供新的思路。
胸腺基质淋巴细胞生成素（thymic stromal lymphopoietin，TSLP）是一种主要由皮肤、肺、胸腺与胃肠道等器官的上皮细胞分泌的与IL-7类似的炎性细胞因子。TSLP是一种多功能的细胞因子，可以作用于多种细胞如T细胞、B细胞、DC和肿瘤细胞等，具有重要的生物学功能。近年来，越来越多的研究表明，TSLP能够调控肿瘤的发生发展。一方面，TSLP在结肠癌、皮肤癌以及初期乳腺癌、胰腺癌的发展阶段发挥了重要的抗肿瘤作用；另一方面，TSLP在胃癌、肺癌、子宫颈癌和急性淋巴细胞白血病等恶性肿瘤的发生发展过程中发挥促进肿瘤进展的作用，提示TSLP可作为相关肿瘤治疗的潜在靶点。本文综述了近年来TSLP及其信号通路，以及其与乳腺癌、胰腺癌、子宫颈癌、胃癌、结肠癌、肺癌、皮肤癌、B细胞急性淋巴细胞白血病等多种恶性肿瘤发生发展的关系的研究进展，旨在为相关肿瘤的诊断和治疗提供新的思路。
2017, 24(1):97.
DOI: 10.3872/j.issn.1007-385X.2017.01.018
Abstract:
维持适当的氧含量对机体的生存至关重要，但是在许多病理情况下，细胞和组织器官经常会处于一种缺氧的状态，此时细胞需要通过缺氧诱导因子（hypoxia-inducible factors，HIF）途径来适应缺氧的环境。肿瘤细胞的过度生长会限制肿瘤内的氧气弥散，导致肿瘤内血液供应不足，产生缺氧的微环境，进而促进HIF的表达。HIF具有广泛的下游基因，与多种信号通路有关，参与肿瘤血管的形成、维持肿瘤干细胞的稳定、促进肿瘤转移，并与肿瘤的预后相关，在肿瘤的发生发展中起到至关重要的作用，有望为肿瘤的精准治疗提供新的靶点和思路。
维持适当的氧含量对机体的生存至关重要，但是在许多病理情况下，细胞和组织器官经常会处于一种缺氧的状态，此时细胞需要通过缺氧诱导因子（hypoxia-inducible factors，HIF）途径来适应缺氧的环境。肿瘤细胞的过度生长会限制肿瘤内的氧气弥散，导致肿瘤内血液供应不足，产生缺氧的微环境，进而促进HIF的表达。HIF具有广泛的下游基因，与多种信号通路有关，参与肿瘤血管的形成、维持肿瘤干细胞的稳定、促进肿瘤转移，并与肿瘤的预后相关，在肿瘤的发生发展中起到至关重要的作用，有望为肿瘤的精准治疗提供新的靶点和思路。
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Supported by:Beijing E-Tiller Technology Development Co., Ltd.